Sterility is an essential characteristic of injectable and ophthalmic pharmaceutical products. This characteristic is imparted to the product by virtue of the type of manufacturing process. If during the process, all components, solutions and equipment are pre-sterilized and assembled aseptically, that is, using techniquies which exclude microorganisms, the product is deemed an "aseptic fill". Other injectable products, in addition to the aseptic processing, undergo sterilization when in the final container, typically using steam under pressure. This procedure, if properly designed and executed, results in a terminally sterilized product.
Regardless of the process which yields a sterile product, the characteristic of sterility must be evaluated and adjudged according to an established criterion, using an accepted method. One such method is set forth in the United States Pharmacopeia ("USP"). The UPS recognizes the sterility test as a referee method and one indication of the acceptable performance of the manufacturing process.
A sterility test using membrane filtration described in the UPS involves aseptically opening a number of final product containers, removing the contents, and filtering the product through a bacterial retentive filter. The filter, with any adherent viable microbial cells, is then placed into a microbiological growth medium; it is incubated for a specified period of time, usually 7 to 14 days, and observed regullary for evidence of microbial growth.
In performing the sterility test, care must be exercised to assure the validity of the test. Some of the measures taken to assure proper aseptic technique include the following: all materials used in the test such as forceps, scissors, and the testing apparatus are pre-sterilized. The growth media and the solutions used to rinse membranes are sterilized by autoclaving. Further, the outside of the product containers are disinfected prior to entering the test facility. The test is conducted in a clean room in a certified HEPA filtered, laminar flow hood. To assure the quality of the environment, the area is regularly sanitized and during the test, air quality if monitored. Testing is conducted by personnel, trained in aseptic techniques, who are appropriately dress in clean, sterilized low shedding garments. Finally, negative controls are incorporated into the testing procedure to monitor the quality of the reagents, equipment, and the technique. These stringent procedures are essential for the protection of the product and the environment to prvent the occurrence of extraneou or advetitious contamination.
Although a positive result in a sterility test due to adverntitous contamination may be invalidated because the contamination can be attributed to analytical error, the reality experienced by those involved in interpreting sterility test results is the uncertaintyinherent in assigning the source of contamination to either the testing procedure or to the manufacturing process. There are rarely clear cut ases in which contamination can be attributed "without a shadow of a doubt" to either analytical error, leading to invalidation of the test, or to the manufacturing operation resulting in rejection of the material.
Thus one problem encountered in sterility testing is the need to reduce exposure of the product and the environment to personnel. The transfer of product to the membrane involves many manipulations, each of which could potentially introduce contamination.
One solution to the problems incurred through human contamination is through automation of the sterility test procedure. However, because of the variety of dosage forms testes, that is, ampules, vials, etc., and because of the variety of sizes which have to be accommodated, automation is difficult to accomplish.
A paper entitled, "A Robotic System for the Sterility Testing of Injectables," Barbara J. Zlotnick and Michael L. Franklin, Pharmaceutical Technology, May 1987, describes a robotic system for sterility testing of vials. According to this paper a robot is used to perform sterility testing and minimize the manipulations performed by the analyst, thereby reducing the potential for technical contamination attributable to personnel. Since human intervention is minimized during testing, the environment of the test remains cleaner with respect to viable particulate matter. There is a lower level of human activity and less potential for contamination from shedding or from disruption of the laminarity of the air flow under the hood. A cleaner environment can then be used for a greater proportion of the work day.
While this robotic system is suitable for the sterility testing of product vials it is not entirely satisfactory for the testing of ampules.
Ampules are sealed glass containers having a narrow neck which is scored to permit easy breaking. To open an ampule, the body of the ampule is held while sideways pressure is applied to the head until the head breaks off along the scoreline at the neck. The requirement for manual opening of each ampulte increases the chance of the afore-described technical contamination and thereby reduces the advantages gained by utilizing a robotic sterility test system.